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Sarcoidosis

Basics

Description

  • Sarcoidosis is a noninfectious, multisystem, granulomatous disease of unknown cause, commonly affecting young and middle-aged adults.
    • Frequently presents with hilar adenopathy, pulmonary infiltrates, ocular or skin lesions
    • In ~50% of cases, it is diagnosed in asymptomatic patients with abnormal chest x-rays (CXRs).
    • Almost any organ may be involved.
  • System(s) affected: primarily pulmonary but also cardiovascular, gastrointestinal, hematologic/lymphatic, endocrine, renal, neurologic, dermatologic, ophthalmologic, musculoskeletal
  • Synonym(s): Löfgren syndrome (erythema nodosum [EN], hilar adenopathy, fever, arthralgias); Heerfordt syndrome (uveitis, parotid enlargement, facial palsy, fever); Besnier-Boeck disease; Boeck sarcoid; Scheuermann disease (1)[C],(2)[B],(3)[C]

Epidemiology

Incidence
Estimated 6/100 person-years (3)

Prevalence
  • Estimated 10 to 20/100,000 persons
  • 11/100,000 annual incidence rate for women (4)
  • Usually occurs in younger persons, although in a single center medical record review in Minnesota, the peak age of incidence for women was 50 to 69 years and for men 40 to 59 years (5)
  • Rare in children (2,3)
  • In the United States, the highest prevalence is in the Northeast (4).

Etiology and Pathophysiology

  • Despite extensive research, mostly unknown
  • Thought to be due to exaggerated cell-mediated immune response to unknown antigen(s)
  • In the lungs, the initial lesion is CD4+ T-cell alveolitis, causing noncaseating granulomata, which may resolve or may undergo fibrosis.
  • “Immune paradox” with affected organs showing an intense immune response and yet anergy exists elsewhere (1)[C]

Genetics
  • Reports of familial clustering, with genetic linkage to a section within MHC on short arm of chromosome 6
  • 3 to 4 times more common in African Americans
  • Although worldwide in distribution, increased prevalence in Scandinavians, Japanese, African Americans, and women
  • In Northern Europe, 5 to 40 cases per 100,000 persons. In Black Americans, 35 cases per 100,000 persons; in Caucasian Americans, 11 cases per 100,000 persons (3)[C]

Risk Factors

Exact etiology and pathogenesis remain unknown.

General Prevention

None

Commonly Associated Conditions

None

Diagnosis

History

  • Patients may be asymptomatic.
  • Patients may have nonspecific complaints, such as the following:
    • Nonproductive cough
    • Shortness of breath
    • Fever
    • Night sweats
    • Weight loss
    • General fatigue
    • Eye pain
    • Chest pain/palpitations
    • Skin lesions
    • Polyarthritis
    • Renal calculi
    • Facial droop due to Bell palsy
    • Encephalopathy, seizures, hydrocephalus (rare)
    • Patients >70 years old more likely to have systemic symptoms

Physical Exam

  • Many patients have a normal physical exam.
  • Lungs may reveal wheezing/fine interstitial crackles in advanced disease.
  • ~30% of patients have extrapulmonary manifestations (1), which may include the following:
    • Uveitis
    • Other eye findings: conjunctival nodules, lacrimal gland enlargement, cataracts, glaucoma, papilledema
    • Cranial nerve palsies
    • Salivary gland swelling
    • Lymphadenopathy
    • Arrhythmias
    • Hepatosplenomegaly
    • Polyarthritis
    • Rashes (1)
      • Maculopapular of nares, eyelids, forehead, base of neck at hairline, and previous trauma sites
      • Waxy nodular of face, trunk, and extensor surfaces of extremities
      • Plaques (lupus pernio) of nose, cheeks, chin, and ears
      • EN (component of Löfgren syndrome)
      • Atypical lesions

Differential Diagnosis

  • Sarcoidosis is a diagnosis of exclusion.
  • Infectious granulomatous disease, such as tuberculosis and fungal infections
  • Hypersensitivity pneumonitis
  • Lymphoma
  • Other malignancies associated with lymphadenopathy
  • Berylliosis (1)[C]

Diagnostic Tests & Interpretation

No definitive test for diagnosis, but diagnosis is suggested by the following:

  • Clinical and radiographic manifestations
  • Exclusion of other diagnoses
  • Histopathologic detection of noncaseating granulomas
Initial Tests (lab, imaging)
  • CBC: Anemia/leukopenia ± eosinophilia can be seen.
  • Hypergammaglobulinemia can exist.
  • LFTs: Abnormal liver function and increased alkaline phosphatase can be encountered with hepatic involvement.
  • Calcium: Hypercalciuria occurs in up to 10% of patients, with hypercalcemia less frequent.
  • Serum ACE elevated in >75% of patients but is not diagnostic or exclusionary
    • Drugs may alter lab results: Prednisone will lower serum ACE and normalize gallium scan. ACE inhibitors will lower serum ACE level.
    • Disorders may alter lab results: Hyperthyroidism and diabetes will increase serum ACE level.
  • CXR or CT scan may reveal granulomas/hilar adenopathy. Routine CXRs are staged using Scadding classification.
    • Stage 0 = normal
    • Stage 1 = bilateral hilar adenopathy alone
    • Stage 2 = bilateral hilar adenopathy + parenchymal infiltrates
    • Stage 3 = parenchymal infiltrates alone (primarily upper lobes)
    • Stage 4 = pulmonary fibrosis (1,2)[C]
  • Chest CT scan may enhance appreciation of lymph nodes.
  • High-resolution chest CT scan may reveal peribronchial disease.
  • Gallium scan will be positive in areas of acute disease/inflammation but is not specific.
  • Positron emission tomography (PET) scan can indicate areas of disease activity in lungs, lymph nodes, and other areas of the body but does not differentiate between malignancy and sarcoidosis.
  • Cardiac PET scan may detect cardiac sarcoidosis (2,3)[C].
  • Serum amyloid A and adenosine deaminase has been found to be elevated with sarcoidosis but are not clinically used due to low sensitivity and specificity (6)[C].
Diagnostic Procedures/Other
  • Pulmonary function tests (PFTs) may reveal restrictive pattern with decreased carbon monoxide diffusing capacity (DLCO).
  • Characteristically in active disease, bronchoalveolar lavage fluid has an increased CD4-to-CD8 ratio.
  • Ophthalmologic examination may reveal uveitis, retinal vasculitis, or conjunctivitis.
  • ECG
  • Tuberculin skin test
  • Biopsy of lesions should reveal noncaseating granulomas.
  • If lungs are affected, bronchoscopy with biopsy of central and peripheral airways is helpful. Endobronchial US (EBUS)–guided transbronchial needle aspiration may potentially have a better diagnostic yield (2)[C].
  • Kveim test (ongoing research): Suspension of sterilized splenic cells from a patient with sarcoidosis is injected in an intradermal skin test to evoke a sarcoid granulomatous response over 3 weeks, similar to a tuberculin skin test.

ALERT
If signs indicate Löfgren syndrome (acute sarcoid with bilateral hilar lymphadenopathy, EN, and diffuse arthritis/arthralgias), it is not necessary to perform a biopsy because prognosis is good with observation alone, and biopsy would not change management.

Test Interpretation
Noncaseating epithelioid granulomas without evidence of fungal/mycobacterial infection

Treatment

  • Many patients undergo spontaneous remission. It is difficult to assess disease activity and severity, however, making it challenging to develop guidelines.
  • No treatment may be necessary in asymptomatic individuals, but treatment may be needed for specific indications, such as cardiac, CNS, renal, or ocular involvement.
  • No treatment is indicated for asymptomatic patients with stage I to III radiographic changes with normal/mildly abnormal lung function, although close follow-up is recommended.
  • Treatment of pulmonary and skin manifestations is done on the basis of impairment. The symptoms that necessitate systemic therapy remain controversial.
    • Worsening pulmonary symptoms
    • Deteriorating lung function
    • Worsening radiographic findings (7)[B]

Medication

Systemic therapy is clearly indicated for hypercalcemia, cardiac disease, neurologic disease, and eye disease not responding to topical therapy. Most patients with pulmonary sarcoidosis do not require treatment with medications because many are asymptomatic or have a spontaneous remission.

First Line
  • There is no FDA-approved treatment specifically for sarcoidosis.
  • Systemic corticosteroids in the symptomatic individual (dyspnea, cough, hemoptysis) or in the individual with worsening lung function or radiographic findings
    • The optimal dose of glucocorticoids is not known.
    • Usually prednisone initially, 0.3 to 0.6 mg/kg ideal body weight (20 to 40 mg/day) for 4 to 6 weeks
    • If stable, taper by 5 mg/week to 10 to 20 mg/day over the next 6 weeks.
    • If no relapse, 10 to 20 mg/day for 8 to 12 months
    • Relapse is common.
    • Higher doses (80 to 100 mg/day) may be warranted in patients with acute respiratory failure and cardiac, neurologic, or ocular disease.
  • In patients with skin disease, topical steroids may be effective.
  • Inhaled steroids (budesonide 800 to 1,600 μg BID) may be of some clinical benefit in early disease with mild pulmonary symptoms.
    • Contraindications: patients with known problems with corticosteroids
    • Precautions: careful monitoring in patients with diabetes mellitus and/or hypertension
    • Significant possible interactions: Refer to the manufacturer’s profile of each drug (1,3,7)[C].
Second Line
  • All alternative agents to glucocorticoids carry substantial risk for toxicity, including myelosuppression, hepatotoxicity, and opportunistic infection. Prior to utilizing these medications, it is important to assess for steroid compliance, comorbid disease, or other complicating factors contributing to steroid failure.
  • Methotrexate: initially 7.5 mg/week, increasing gradually to 10 to 15 mg/week
  • Azathioprine: generally a supplement to prednisone in an attempt to lower steroid doses
  • Leflunomide
  • Mycophenolate
  • Use of immunosuppressants, such as methotrexate or azathioprine, will require regular monitoring of CBC and LFTs.
  • Antimalarial agents, such as chloroquine or hydroxychloroquine
  • Tumor necrosis factor antagonists, such as infliximab, have been useful in refractory cases (3,7)[C].

Issues For Referral

May be followed by a pulmonologist, with referrals to other specialists as dictated by involvement of other organ systems; if requiring a second-line therapy, should be followed by a specialist.

Surgery/Other Procedures

Lung transplantation in severe, refractory cases; long-term outcomes are unknown.

Complementary and Alternative Medicine

None known to be effective

Ongoing Care

Follow-up Recommendations

There is limited data on indications for the specific tests and optimal frequency of monitoring of disease activity. Suggestions follow.

Patient Monitoring
  • Patients on prednisone for symptoms should be seen q1–2mo while on therapy.
  • Patients not requiring therapy should be seen regularly (q3mo) for at least the first 2 years after diagnosis, obtaining a thorough history and physical exam, laboratory testing tailored to sites of disease activity, PFTs, and ambulatory pulse oximetry.
  • If active disease
    • Every 6 to 12 months, obtain ophthalmologic exam if on hydroxychloroquine.
    • Annually, CBC, creatinine, calcium, LFTs, ECG, 25-hydroxy vitamin D and 1,25 dihydroxy vitamin D, CXR, ophthalmologic examination
  • Other testing per individual patient’s symptoms, including HRCT, echocardiogram, Holter monitoring, urinalysis (UA), thyroid-stimulating hormone (TSH), bone density, MRI of brain
  • The serum ACE level is used by some physicians to follow the disease activity. In patients with an initially elevated ACE level, it should fall toward normal while on the therapy or when the disease resolves.
  • If inactive disease, follow annually with history and physical exam, PFTs, ambulatory pulse oximetry, CBC, creatinine, calcium, liver enzymes, 1,25 dihydroxy vitamin D, ECG, and ophthalmologic exam.

Diet

No special diet

Patient Education

Prognosis

  • 50% of patients will have spontaneous resolution within 2 years.
  • 25% of patients will have significant fibrosis, but no further worsening of the disease after 2 years.
  • 25% of patients (higher in some populations, including African Americans) will have chronic disease.
  • Patients on corticosteroids for >6 months have a greater chance of having chronic disease.
  • Overall death rate: <5%
  • Rate of hospitalization is higher among patients with sarcoidosis than without sarcoidosis (8)[B].

Complications

  • Patients may develop significant respiratory involvement, including cor pulmonale.
  • Pulmonary hemorrhage from infection with aspergillosis in the damaged lung is possible.
  • Other organs, especially the heart (congestive heart failure, arrhythmias), eyes (rarely blindness), and CNS, can be involved with serious consequences. Cardiac, ocular, and CNS involvement usually manifest early in patients with these complications of the disease.

Additional Reading

Hoang DQ, Nguyen ET. Sarcoidosis. Semin Roentgenol. 2010;45(1):36–42. [PMID:19944251]

Codes

ICD-10

  • D86.0 Sarcoidosis of lung
  • D86.1 Sarcoidosis of lymph nodes
  • D86.2 Sarcoidosis of lung with sarcoidosis of lymph nodes
  • D86.3 Sarcoidosis of skin
  • D86.81 Sarcoid meningitis
  • D86.82 Multiple cranial nerve palsies in sarcoidosis
  • D86.83 Sarcoid iridocyclitis
  • D86.84 Sarcoid pyelonephritis
  • D86.85 Sarcoid myocarditis
  • D86.86 Sarcoid arthropathy
  • D86.87 Sarcoid myositis
  • D86.89 Sarcoidosis of other sites
  • D86.9 Sarcoidosis, unspecified

ICD-9

  • 135 Sarcoidosis
  • 517.8 Lung involvement in other diseases classified elsewhere
  • 713.7 Other general diseases with articular involvement

SNOMED

  • 193251003 Sarcoid myopathy
  • 234526006 Ocular sarcoidosis (disorder)
  • 238675007 Sarcoidosis-induced erythema nodosum (disorder)
  • 24369008 Pulmonary sarcoidosis (disorder)
  • 31541009 Sarcoidosis (disorder)
  • 361198004 Sarcoid arthritis (disorder)
  • 55941000 cutaneous sarcoidosis (disorder)
  • 64757003 lymph node sarcoidosis (disorder)
  • 75403004 Cardiac sarcoidosis

Clinical Pearls

  • Sarcoidosis is a noninfectious, multisystem, granulomatous disease of unknown cause, typically affecting young and middle-aged adults.
  • Any organ can be affected.
  • Diagnosis is based on clinical findings, exclusion of other disorders, and pathologic detection of noncaseating granulomas.
  • Most patients do not need systemic treatment, and the disease resolves spontaneously; a few will have life-threatening progressive organ dysfunction.

Authors


Donnah Mathews, MD

Figures

Figure 13-15

Sarcoidosis.

Bibliography

  1. Baughman RP, Culver DA, Judson MA. A concise review of pulmonary sarcoidosis. Am J Respir Crit Care Med. 2011;183(5):573–581.  [PMID:21037016]
  2. Iannuzzi MC, Fontana JR. Sarcoidosis: clinical presentation, immunopathogenesis, and therapeutics. JAMA. 2011;305(4):391–399.  [PMID:21266686]
  3. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med. 2007;357(21):2153–2165.  [PMID:18032765]
  4. Dumas O, Abramovitz L, Wiley AS, et al. Epidemiology of sarcoidosis in a prospective cohort study of U.S. women. Ann Am Thorac Soc. 2016;13(1):67–71. [PMID:26501211]
  5. Ungprasert P, Carmona EM, Utz JP, et al. Epidemiology of sarcoidosis 1946–2013: a population-based study. Mayo Clin Proc. 2016;91(2):183–188.  [PMID:25623898]
  6. Gungor S, Ozseker F, Yalcinsoy M, et al. Conventional markers in determination of activity of sarcoidosis. Int Immunopharmacol. 2015;25(1):174–179.  [PMID:19857644]
  7. King CS, Kelly W. Treatment of sarcoidosis. Dis Mon. 2009;55(11):704–718. [PMID:19857644]
  8. Ungprasert P, Crowson CS, Achenbach SJ, et al. Hospitalization among patients with sarcoidosis: a population-based cohort study 1987–2015. Lung. 2017;195(4):411–418. [PMID:28456873]


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Citation

Stephens, Mark B., et al., editors. "Sarcoidosis." 5-Minute Clinical Consult, 27th ed., Wolters Kluwer, 2019. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116543/all/Sarcoidosis.
Sarcoidosis. In: Stephens MB, Golding J, Baldor RA, et al, eds. 5-Minute Clinical Consult. 27th ed. Wolters Kluwer; 2019. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116543/all/Sarcoidosis. Accessed June 27, 2019.
Sarcoidosis. (2019). In Stephens, M. B., Golding, J., Baldor, R. A., & Domino, F. J. (Eds.), 5-Minute Clinical Consult. Available from https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116543/all/Sarcoidosis
Sarcoidosis [Internet]. In: Stephens MB, Golding J, Baldor RA, Domino FJ, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2019. [cited 2019 June 27]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116543/all/Sarcoidosis.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Sarcoidosis ID - 116543 ED - Stephens,Mark B, ED - Golding,Jeremy, ED - Baldor,Robert A, ED - Domino,Frank J, BT - 5-Minute Clinical Consult, Updating UR - https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116543/all/Sarcoidosis PB - Wolters Kluwer ET - 27 DB - Medicine Central DP - Unbound Medicine ER -